The TDG protein environment connects active DNA demethylation with chromatin and RNA biology

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Detalles Bibliográficos
Publicado en:	Cellular and Molecular Life Sciences vol. 83, no. 1 (Dec 2026), p. 15
Autor principal:	Richina, Federica
Otros Autores:	Noreen, Faiza, Bauer, Christina, Weber, Alain, Kunz, Christophe, Buczak, Katarzyna, Schwarz, Simon D., Wu, Fabian, Schürmann, David, Schär, Primo
Publicado:	Springer Nature B.V.
Materias:	DNA methylation rRNA Embryo cells Tethering Methyltransferase Thymine Humidity Histones Ribonucleic acid > RNA Stem cells DNA glycosylase Chromatin remodeling Genomes Non-coding RNA Epigenetics Hybrids Demethylation Proteins Plasmids Oxidation Thymine DNA glycosylase Functional morphology Gene expression RNA-binding protein Cloning Deoxyribonucleic acid > DNA Proteomes RNA processing R-loops Environmental
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Descripción
Resumen:	Understanding the interplay between DNA methylation and gene expression remains a challenge. This study explores the proteome of active DNA demethylation in murine embryonic stem cells (mESC), focusing on the base-excision-repair (BER) step initiated by the Thymine DNA Glycosylase (TDG). Using BioID2 proximity labeling, we identified a TDG interactome encompassing four functional aspects: chromatin organization and transcription, chromosomal organization, RNA processing, and ribosomal biogenesis. We show specifically that TDG participates in a genome regulatory network involving chromatin remodelers and modifiers such as RUVBL2 and the H3K4 methyltransferase complex tethering factor HCFC1, consistent with the dysregulation of histone modifications observed in TDG-deficient cells. We also identified the paraspeckle components PSPC1 and NONO as TDG interactors, implicating TDG in RNA-mediated nuclear processes. This led us to show that TDG is an RNA-binding protein, interacting with long-noncoding RNAs (lncRNA), including the paraspeckle organizing lncRNA Neat1, previously reported to target TET proteins to genomic sites and to engage in R-loop regulation. We then demonstrate TDG’s ability to excise oxidized 5-methylcytosine in RNA:DNA hybrids, suggesting a role of active DNA demethylation in the regulation of R-loops. Our findings thus unveil a direct crosstalk between active DNA demethylation, chromatin modification and remodeling as well as RNA-genome interactions in mESC, providing avenues for future mechanistic investigations.
ISSN:	1420-682X 1420-9071 0014-4754
DOI:	10.1007/s00018-025-05943-y
Fuente:	Health & Medical Collection